U.S. patent application number 10/681938 was filed with the patent office on 2005-04-14 for liposomal delivery system for topical pharmaceutical, cosmeceutical, and cosmetic ingredients.
Invention is credited to Gupta, Shyam K..
Application Number | 20050079210 10/681938 |
Document ID | / |
Family ID | 34422396 |
Filed Date | 2005-04-14 |
United States Patent
Application |
20050079210 |
Kind Code |
A1 |
Gupta, Shyam K. |
April 14, 2005 |
Liposomal delivery system for topical pharmaceutical,
cosmeceutical, and cosmetic ingredients
Abstract
A method of producing a lipophilic liposomal composition
includes the step of forming a liposome forming composition by
admixing at an elevated temperature at least one lipophilic
ingredient selected from a group consisting of pharmaceutical
lipophilic ingredients, cosmetic lipophilic ingredients, and
cosmeceutical lipophilic ingredients; a liposome-forming lipid
component; and, a solubliizer for the liposome-forming lipid
component. The resulting liposome forming composition is then
cooled.
Inventors: |
Gupta, Shyam K.;
(Scottsdale, AZ) |
Correspondence
Address: |
TOD R. NISSLE, P.C.
P.O. Box 55630
Phoenix
AZ
85078
US
|
Family ID: |
34422396 |
Appl. No.: |
10/681938 |
Filed: |
October 9, 2003 |
Current U.S.
Class: |
424/450 |
Current CPC
Class: |
A61K 47/32 20130101;
A61K 47/16 20130101; A61K 9/127 20130101 |
Class at
Publication: |
424/450 |
International
Class: |
A61K 009/127 |
Claims
I claim:
1. A method of producing a lipophilic liposomal composition,
comprising the steps of (a) forming a liposome forming composition
by admixing at an elevated temperature (i) at least one lipophilic
ingredient selected from a group consisting of pharmaceutical
lipophilic ingredients, cosmetic lipophilic ingredients, and
cosmeceutical lipophilic ingredients, (ii) a liposome-forming lipid
component, and (iii) a solubliizer for said liposome-forming lipid
component; (b) cooling said liposome forming composition to form
loaded liposomes.
Description
[0001] This invention pertains to systems for delivering topical
pharmaceutical, cosmeceutical, and cosmetic ingredients.
[0002] More particularly, the invention pertains to a system for
forming liposomal pharmaceutical--cosmeceutical carriers by cooling
a polyamide--solubilizer--lipophilic--cosmetic/pharmaceutical
composition.
[0003] In a further respect, the invention pertains to a system for
forming a liposomal carrier by combining a polyamide and
solubilizer at an elevated temperature, by cooling the resulting
composition, and by adding a cosmetic--pharmaceutical ingredient to
cause the spontaneous production of liposomes.
[0004] The use of liposomes as delivery systems for cosmetics and
pharmaceuticals has been known for some time.
[0005] A liposome is also defined as a hollow spherical colloidal
structure consisting of one or more concentric phospholipid
bilayers separated by water or aqueous buffer compartments. Hollow
liposome structures also have an internal aqueous compartment.
Liposomes can be prepared in diameters ranging from 20 nm
(nanometers) to 10 microns, and are classified according to their
final size and preparation method. For example, SUV liposomes are
small unilamellar vesicles (0.5-50 nm). LUV liposomes are large
unilamellar vesicles (100 nm). REV liposomes are reverse phase
evaporation vesicles (0.5 micrometer). MLV liposomes are large
mutlilamellar vesicles (21-10 micrometers). Drug molecules can
either be encapsulated in the enclosed aqueous space or be
intercalated into the lipid bilayer.
[0006] The exact location of a cosmetic or drug ingredient in a
liposome depends on its physicochemical characteristics and the
composition of the lipids in the liposome.
[0007] Liposomes are effective for sustained release of drug or
cosmetic ingredients, but have the drawback that the amount of such
ingredients that can be contained in the liposome is limited. One
difficulty encountered in the preparation of such sustained release
liposomes is producing liposomes that are stable. Another
difficulty is producing liposomes that have a high concentration of
a desired ingredient. A further difficulty is that all types of
unilamellar vesicles and single bilayer liposomes have a relatively
low content of lipid molecules and, consequently, have a low
loading capacity for lipophilic compounds. Such liposomes are more
suitable for the entrapment of water-soluble materials.
Multilamellar liposomes can be used to encapsulate large amount of
hydrophobic ingredients, but are not appropriate for many topical
or pharmaceutical applications because their large size prevents
absorption into the skin and they tend to be unstable.
[0008] Various methods have been reported for preparing
conventional liposomes and for using liposomes to apply topically
pharmaceutical, cosmetic, and cosmeceutical ingredients. Drawbacks
of conventional liposomes include their instability during storage,
low reproducibility during manufacture, low entrapment efficiency,
and leakage of loaded ingredients from the liposomes.
[0009] Unconventional liposomes sometimes remedy the drawbacks of
conventional liposomes. One two-phase process makes liposomes in
which one phase is a water-immiscible organic solvent and the other
phase is an aqueous phase. This manufacturing process requires,
however, a complex balance of solvent ratio, mixing speed,
temperature, and an inert gas flow that are mathematically
calculated. The process is impractical in normal production
environments.
[0010] Another unconventional liposome is a combination of a
soluble polysaccharide and lipophilic material incorporated in
spherical beads that are loaded with skin beneficial ingredients.
The preparation of the spherical beads still requires, however, two
processing steps, which limits commercial applications of the
beads.
[0011] A further unconventional liposome is prepared from
amphiphilic materials. The manufacturing process for amphiphilic
liposomes is complex and of limited scope.
[0012] Other liposomes include cationic lipid compounds. Such have
been conjugated in a variety of moieties including, for example,
carboxyspermine that is conjugated to one of two types of lipids
and includes compounds such as 5-carboxyspermylglycine
dioctyloleoylamide ("DOGS") and
dipalmitoyl-phosphatidylenthanolamine 5-carboxyspermylamide
("DPPES"). Of the cationic lipids that have been proposed for use
in delivering biomolecules to cells, no particular cationic lipid
has been reported to work well with a wide variety of ingredients.
Since cell types differ from one another in membrane composition,
different cationic lipid compositions and different types of lipid
aggregates may be effective for different cell types, either due to
their ability to contact and fuse with target cell membranes
directly or due to different interactions with intracellular
membranes or the intracellular environment. For these and other
reasons, design of effective lipids, including cationic lipids, has
largely been empirical. I addition to content and transfer, other
factors believed important include, for example, ability to form
lipid aggregates suited to the intended purpose, toxicity of the
composition to the target cell, stability as a carrier for the
biomolecule to be delivered, and function in an in vivo
environment.
[0013] Therefore, there is a need for improved liposomes that are
capable of delivering on skin surfaces with greater absorption and
bioavailability cosmetic and pharmaceutical ingredients to a wide
variety of cell types.
[0014] It would be highly desirable to develop an unconventional
liposome system (1) in which liposomes are made in a single-phase
system, (2) in which the liposomes can be loaded with relatively
large amounts (5% to 50% for example) of lipophilic cosmetic and
pharmaceutical ingredients, (3) using a non-aqueous system; (4)
using a simple manufacturing process, (5) to deliver a wide variety
of various lipophilic ingredients, (6) in which the size of
liposome particles is not critical, and (7) using liposomes that
can change their size by the application of mechanical force to
facilitate the application of liposomes to skin or to facilitate
delivering the liposomes from a dispensing system that has a narrow
orifice.
[0015] I have discovered a surprisingly simple preparation of an
acyl amino acid amide based liposome that is electrically neutral
and that is therefore useful for the topical delivery of a wide
variety of lipophilic ingredients. The lipophilic ingredients can
be electrically positive, negative, or neutral; are not limited to
any specific chemical structural moieties or cellular surfaces on
skin; and, can be loaded in the liposomes in large concentrations
in, for example, the range of 5% to 50% by weight. Other features
of the invention are that the liposomal formulations can contain
high levels, such as up to 80% by weight, of a vegetable oil as a
carrier or solubilizer ingredient; the liposomal formulations do
not feel oily on skin surface; and, the liposomal formulations are
rapidly absorbed into the skin. It is theorized that the
amide-based liposomes carry a lipophilic "tail" that is believed to
help the rapid absorption of oily and lipophilic ingredients used
in the system of the invention.
[0016] I have also discovered a liposome and method of forming the
same by forming a liposomal composition by combining at an elevated
temperature a polyamide plus a solubilizer plus a lipophilic
cosmetic/pharmaceutical ingredient, and then by cooling the
composition to cause liposomes to form. The elevated temperature is
in the range of 30 degrees C. to 150 degrees C., preferably 70
degrees C. to 120 degrees C.
[0017] I have also discovered a liposome and method of forming the
same by forming a composition by combining a polyamide plus a
solubilizer at an elevated temperature, by cooling the composition,
and by addiing a lipophilic cosmetic/pharmaceutical ingredient to
cause the spontaneous formation of the liposome. The elevated
temperature is in the range of 30 degrees C. to 150 degrees C.,
preferably 70 degrees C. to 120 degrees C.
[0018] As used herein, the terms listed below have the meanings set
forth therewith.
[0019] Cosmeceutical ingredient. A cosmetic ingredient that may
have the efficacy of a pharmaceutical ingredient.
[0020] Cosmetic ingredient. An ingredient that is used in the
composition of a cosmetic product and that has no permanent or
long-term biological benefits.
[0021] Disease. An abnormal condition of an organism or part,
especially as a consequence of infection, inherent weakness or
environmental stress, that impairs normal physiological
functioning.
[0022] Drug. A substance that is used in the treatment of disease,
and that in many cases has a permanent or long-term biological
benefit.
[0023] Lipophilic. Soluble with fats or lipids.
[0024] Pharmaceutical ingredient. A drug.
[0025] The lipophilic cosmetic, cosmeceutical, or pharmaceutical
ingredient(s) used in the invention can, by way of example and not
limitation, be selected from a group consisting of emollients, skin
rejuvenating agents, antioxidants, anti-inflammatory agents,
antibacterial agents, antifungal agents, topical analgesic agents,
local anesthetics, hormones, vitamins, nutraceutical agents, skin
whitening agents, and botanical extracts.
[0026] The liposome-forming lipid(s) used in the invention can, by
way of example and not limitation, be selected from a group
consisting of an acyl amino acid amide (N-acyl glutamic acid
diamide, for example), a siloxane-based polyamide, or from a number
of polyamides marketed by Arizona Chemical under various trade
names like Sylvaclear, Sylvaclear Lightwax, and Sylvaclear
PA20.
[0027] The solubilizer for a liposome forming lipid component(s)
can, by way of example and not limitation, be selected from a group
consisting of methyl soyate alkyl benzoate esters, methyl cocate,
polypropylene glycols, various vegetable oils, and other
solubilizers of liposome forming lipid components.
[0028] The compositions of the invention can include a carrier(s)
selected from a variety of common lipophilic emollients and that
can, by way of example and not limitation, be selected from a group
consisting of C12-15 alkyl benzoate, behenyl benzoate, castor oil
benzoate, isopropyl myristate, isopropyl palmitate, isopropyl
oleat, isopropyl stearate, methyl soyate, silicone gums, olive oil,
almond oi, sesame oil, coconut oil, polypropylene glycol, propylene
glycol ethers, diocytl adipate, dioctyl succinate, and dioctyl
fumarate. The carrier can be incorporated before, during, or after
formation of liposomes.
[0029] The lipophilic pharmaceutical, cosmetic, or cosmeceutical
ingredient(s) can, by way of example and not limitation, be
selected from a group consisting of vitamin E, vitamin E acetate,
Tocotrienol, Progesterone, Capsaicin, Capsicum oleoresin, menthol,
methyl salicylate, benzophenone-3, octyl methoxycinnamate,
Benzocaine, and Lidocaine. The weight percent of the lipophilic
ingredient in the liposomes of the invention is in the range of
0.01% to 55%, preferably 5% to 50%.
[0030] The following examples are given by way of illustration and
not limitation of the invention.
EXAMPLE 1
[0031] This example illustrates the use of methyl soyate to
function both as a carrier for loading liposomes and as a
solubilizer of liposome forming lipid components.
[0032] The following components are provided:
1 Item Component Weight % 1. Methyl soyate (a carrier) 55.4 2.
Propyl paraben (a preservative) 0.2 3. Methyl soyate (a
solubilizer) 3.0 4. N-acyl glutamic acid diamide (a liposome- 0.5
forming lipid component) 5. Vitamin E acetate 40.0 6. Kiwi fruit
seed oil 0.1 7. Grape seed oil 0.1 8. Rose hip oil 0.1 9. Evening
primrose oil 0.1 10. Fragrance 0.5
[0033] Step Procedure
[0034] A. Mix items 3 and 4 and heat at a temperature in the range
of 90 degrees C. to 110 degrees C. to produce a solution.
[0035] B. Mix items 1, 2, 6, 7, 8, and 9 and heat to a temperature
in the range of 60 degrees C. to 70 degrees C. to form a
composition.
[0036] C. Admix the solution of step A with the composition of step
B and begin cooling the resulting mixture to a temperature in the
range of 40 degrees C. to 50 degrees C. Liposomes do not form
during cooling because during cooling there is no mixing or there
is only very gentle mixing.
[0037] D. Ddd item 5 to the cooled mixture of Steps C, D. Mix
gently. Item 5 is rapidly absorbed into the liposomes to form a
liposomal mixture. Liposomes loaded with Item 5 are spontaneously
formed. The liposomes are visible to the naked eye.
[0038] E. Add item 10 to the liposomal mixture of step E and mix
gently to form a final liposomal mixture.
[0039] F. F. Dispense the liposomal mixture of step F into bottles
and mount a pump nozzle on each bottle.
[0040] G. G. Operate the pump nozzle on a bottle to dispense the
liposomal mixture from the bottle. Liposomes in the liposomal
mixture become smaller and are dispensed by the pump nozzle.
EXAMPLE 2
[0041] This example illustrates the use of a lipophilic carrier
that is different from the solubilizer of the liposome forming
lipid component.
[0042] The following components are provided:
2 Item Component Weight % 1. C12-15 alkyl benzoate (a carrier) 90.4
2. N-acyl glutamic acid diamide (a liposome- 1.0 forming lipid
component) 3. Vitamin E acetate 1.0 4. Grape seed oil 0.1 5. Rose
hip oil 0.1 6. Evening primrose oil 0.1 7. LiquaPar (preservative)
0.3 8. Methyl soyate (solubilizer) 5.0 9. Progesterone (a
pharmaceutical lipophilic ingredient) 1.0 10. Fragrance 1.0
[0043] Step Procedure
[0044] A. Mix items 1 and 2 and heat at a temperature in the range
of 90 degrees C. to 110 degrees C. to produce a solution.
[0045] B. Mix items 3, 4, 5, 6, 7, 8, and 9 and heat to a
temperature in the range of 30 degrees C. to 40 degrees C. to form
a composition.
[0046] C. Cool the solution of step A to a temperature in the range
of 40 degrees C. to 50 degrees. Liposomes do not form during
cooling because during cooling there is no mixing or is only very
gentle mixing.
[0047] D. Add the cooled solution of step C to the composition of
step B and mix gently to form a mixture. Loaded liiposomes form
spontaneously and are visible to the naked eye.
[0048] E. Add item 10 to the mixture of step D and mix gently. A
clear gel product is formed with loaded liposomes suspended in the
gel.
[0049] F. Dispense the liposomal mixture of step F into bottles and
mount a pump nozzle on each bottle. On further cooling the liposome
gel sets up as a clear gel with visible liposome particles.
[0050] G. Operate the pump nozzle on a bottle to dispense the
liposomal mixture from the bottle. Liposomes in the liposomal
mixture become smaller and are dispensed by the pump nozzle without
plugging or stoppage.
EXAMPLE 3
[0051] This example illustrates the use of an alternate
liposome-forming lipid component, and illustrates the use of the
same ingredient both as a carrier and as the liposome-forming lipid
solubilizer.
[0052] The following components are provided:
3 Item Component Weight % 1. C12-15 alkyl benzoate (a carrier and
liposome 35.4 forming lipid solubilizer) 2. Syvaclear PA20
(liposome-forming lipid 20.0 component) 3. Vitamin A acetate
(lipophilic cosmeceutical ingredient) 35.0 4. C12-15 Alkyl Benzoate
10.0
[0053] Step Procedure
[0054] A. Mix items 1 and 2 and heat at a temperature in the range
of 60 degrees C. to 70 degrees C. to produce a clear solution.
[0055] B. Cool the solution of step A to a temperature in the range
of 40 degrees C. to 50 degrees C. to form liposomes. Mix during
cooling. Liposomes form because the solution is mixed while it
cools.
[0056] C. Mix items 3 and 4 to form a solution.
[0057] D. Add the cooled solution of step B to the solution of step
C and cool to room temperature. A clear gel with liposomes loaded
with vitamin E acetate is formed.
[0058] E. Dispense the gel into containers.
EXAMPLE 4
[0059] This example illustrates the use of a mixture of vegetable
oils as a carrier for a pharmaceutical ingredient.
[0060] The following components are provided:
4 Item Component Weight % 1. Soybean oil (a carrier) 90.4 2. N-acyl
glutamic acid diamide (a liposome- 0.8 forming lipid component) 3.
Sesame oil 0.5 4. Sweet almond oil 0.5 5. Apricot kernel oil 0.5 6.
Jojoba oil 0.5 7. Mango butter 0.5 8. Shea butter 0.5 9. Rose hip
oil 0.5 10. Macademia oil 0.5 11. Evening primrose oil 0.5 12.
Avocado oil 0.5 13. Progesterone (pharmaceutical ingredient) 2.0
14. Soybean oil 6.0
[0061] Step Procedure
[0062] A. Mix items 1 and 2 and heat at a temperature in the range
of 90 degrees C. to 110 degrees C. to produce a clear solution.
[0063] B. Cool the solution of step A to a temperature in the range
of 40 degrees C. to 50 degrees C. Liposomes do not form during
cooling because during cooling there is no mixing or is only very
very gentle mixing.
[0064] C. Mix items 3 to 14 and heat to a temperature in the range
of 30 degrees C. to 40 degrees C. to form a clear solution.
[0065] D. Add the cooled solution of step B to the solution of step
C and mix gently to instantaneously form visible liposomes loaded
with progesterone.
[0066] F. Cool the liposomal mixture of step D to room temperature
to form a clear gel product with suspended loaded liposomes.
[0067] G. Dispense the clear gel/liposome product of step E into
containers.
EXAMPLE 5
[0068] This example illustrates the versatility of the liposome
system in loading a variety of lipophilic skin beneficial
ingredients in a single step.
[0069] The following components are provided:
5 Item Component Weight % 1. C12-15 alkyl benzoate (a carrier) 88.1
2. Propyl Paraben (preservative) 0.2 3. N-acyl glutamic acid
diamide (a liposome- 0.5 forming lipid component) 4. Tocotrienol
(skin beneficial antioxidant) 5.0 5. Alpha-lipoic acid (skin
beneficial antioxidant) 0.1 6. Coenzyme Q10 (skin beneficial
antioxidant) 0.1 7. Vitamin K (skin beneficial vitamin) 0.1 8. Emu
oil (skin soothing agent) 0.1 9. Panthenol (vitamin) 0.1 10.
Tinoguard TT (preservative) 0.2 11. C12-15 alkyl benzoate (a
solubilizer) 3.0 12. Vitamin E acetate (vitamin) 2.0 13. Kiwi fruit
seed oil (emollient) 0.1 14. Grapeseed oil (emollient) 0.1 15. Rose
hip oil (emollient) 0.1 16. Evening primrose oil (emollient) 0.1
17. Fragrance 0.1
[0070] Step Procedure
[0071] A. Mix items 1 to 3 and heat at a temperature in the range
of 90 degrees C. to 110 degrees C. to produce a clear solution.
[0072] B. Cool the solution of step A to a temperature in the range
of 40 degrees C. to 50 degrees C. Mix the solution while it is
cooling. "Empty" liposomes are formed. Empty liposomes form because
during cooling there is mixing.
[0073] C. Mix items 4 to 17 and heat to a temperature in the range
of 40 degrees C. to 45 degrees C. to form a clear solution.
[0074] D. Add the cooled solution of step B to the solution of step
C and mix gently to produce a mixture. The addition of lipophilic
ingredients to the cooled solution of step B loads the empty
liposomes with organic lipophilic ingredients.
[0075] E. Cool the mixture of step D to room temperature to produce
a clear gel product including loaded liposomes suspended in the
clear gel.
[0076] F. Dispense the clear gel product of step E into
containers.
EXAMPLE 6
[0077] This example illustrates the use of a formulation including
Coenzyme Q10. Coenzyme Q10 is a popular anti-aging ingredient that
is insoluble in many solubilizers. The clear gel liposome product
produced in this example is loaded with solubilized Coenzyme Q10,
has enhanced skin absorption, and provides bioavailable Coenzyme
Q10. This example also illustrates that various skin beneficial
ingredients and vitamins can be simultaneously loaded in liposomes
produced according to the invention.
[0078] The following components are provided:
6 Item Component Weight % 1. Methyl soyate 59.7999 2. N-acyl
glutamic acid diamide (a liposome- 0.5 forming lipid component) 3.
Vitamin E acetate 25.0 4. Grape seed oil 0.1 5. Rose hip oil 0.1 6.
Evening primrose oil 0.1 7. LiquaPar (preservative) 0.3 8. Methyl
soyate (solubilizer) 10.0 9. Progesterone (a pharmaceutical
lipophilic ingredient) 1.0 10. Kiwi fruit seed oil 0.1 11.
Co-enzyme Q-10 2.5 12. Alpha-lipoic acid 0.0001 13. Fragrance
0.5
[0079] Step Procedure
[0080] A. Mix items 1 and 2 and heat at a temperature in the range
of 90 degrees C. to 110 degrees C. to produce a clear solution.
[0081] B. Cool the solution of step A to a temperature in the range
of 40 degrees C. to 50 degrees. Liposomes do not form during
cooling because during cooling there is no mixing or is only very
gentle mixing.
[0082] C. Mix items 4 to 13 and heat to a temperature in the range
of 40 degrees C. to 45 degrees C. to form a clear solution.
Liposomes do not form in the solution.
[0083] D. Add the clear solution of step C to the cooled solution
of step B. Mix gently. The addition of lipophilic ingredients to
the solution of step A causes loaded liposomes to form
spontaneously. A clear gel with suspended liposomes results.
[0084] E. Cool the gel of step D to room temperature.
[0085] F. Dispense the liposomal mixture of step E into
containers.
EXAMPLE 7
[0086] This example illustrates that high levels of oil-soluble
ingredients can be loaded in liposomes produced in accordance with
the invention. In this example, the liposomes contain forty (40%)
percent by weight of vitamin E acetate.
[0087] The following components are provided:
7 Item Component Weight % 1. Methyl soyate (a carrier) 58.0 2.
N-acyl glutamic acid diamide (a liposome- 0.5 forming lipid
component) 3. Vitamin E acetate 40.0 4. Grape seed oil 0.1 5. Rose
hip oil 0.1 6. Pistachio nut oil 0.1 7. LiquaPar (preservative) 0.2
8. Tetrahydrocurcumin 0.5 9. Fragrance 0.5
[0088] Step Procedure
[0089] A. Mix items 1 and 2 and heat at a temperature in the range
of 90 degrees C. to 110 degrees C. to produce a clear solution.
[0090] B. Cool the solution of step A to a temperature of 40
degrees C. to 50 degrees C. Liposomes do not form during cooling
because during cooling there is no mixing or is only very very
gentle mixing.
[0091] C. Mix items 3 to 9 to form a clear solution.
[0092] D. Mix the cooled solution of step B with the solution of
step C. The addition of lipophilic ingredients to the cooled
solution of step B causes loaded liposomes to formed spontaneously
and a clear gel results in which liposomes are suspended in the
gel. The solution of A is cooled because the lipophilic ingredients
that are loaded into the liposomes typically are unstable at higher
temperatures.
[0093] E. Cool the gel of step D to room temperature.
[0094] F. Dispense the liposomal gel of step E into containers.
[0095] Having described my invention in such terms as to enable
those of skill in the art to make and practice it, and having
described the presently preferred embodiments thereof,
* * * * *